Tracking the genome diversity and evolution of virus like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the hotspot of current researches, which were essential for the developing of prevention strategies and therapeutic vaccines. In the current study, a total of 206073 oral or nasopharyngeal swab specimens were collected in 2022 from entry populations originated from Hong Kong, among which 141 whole genome sequences were obtained through next-generation sequencing and analyzed. Two major Omicron sub-lineages were identified: BA.2.2 (70.21%, 99/141) and BA.5 (24.11% 34/141). An average of 53.22 mutations was emerged in the genome, with S protein and ORF1a harboring the highest number of mutations among structure proteins and non-structure proteins (p<0.001), respectively, making them the most variable regions. The temporal changes of the mutations among each protein were unique, indicating the distinct evolution pattern of these proteins. A novel mutation in the Nsp5 (3 C-like proteinase) was reported for the first time. As it may influence the viral replication and transcription, further monitoring is needed. The data reported here highlighted the importance of monitoring the SARS-CoV-2 genome and would be useful for the generation of evidence-based prevention programs and effective vaccines to COVID-19.